Integrin β5-positive cancer-associated fibroblasts promoting lung adenocarcinoma invasion leading to poor prognosis

Abstract

Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment that interact with tumor cells to promote cancer progression, including lung adenocarcinoma (LUAD). Cell adhesion molecules such as integrins play a crucial role in these interactions; however, the clinicopathological significance of integrin expression in LUAD-associated CAFs remains unclear. Hence, we evaluated the expression of integrins α2, α11, β1, and β5, which have been implicated in the progression of other cancer types, in LUAD specimens from 138 patients using immunohistochemistry. Patients with integrin α2-positive CAFs exhibited fewer adverse pathological prognostic factors. Conversely, integrin α11-, β1-, and β5-positive groups demonstrated poor pathological prognostic factors. Notably, the integrin β5-positive group had larger tumor size, higher recurrence rates, and poorer disease-free survival rates. Integrin β5 expression in CAFs was higher than that in normal fibroblasts in vitro. Knockdown of integrin β5 by siRNA transfection suppressed the invasion of co-cultured adenocarcinoma cells. Results from the cytokine antibody array suggest that monocyte chemoattractant protein-1 (MCP-1) and tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) enhance invasion. Inhibition of the MAPK pathway also suppressed adenocarcinoma cell invasion by reducing soluble factors, including MCP-1 and TIMP-1. These findings demonstrate that integrin β5 in CAFs promotes lung adenocarcinoma invasion, leading to poor prognosis. Therefore, targeting integrin β5 in CAFs may improve LUAD outcomes.